Rheumatoid arthritis (RA) is thought to be an autoimmune disease in which T cells erroneously attack hyaline cartilage matrix proteins like, for example type II collagen. Amongst the autoantigens implicated in RA, a novel candidate target antigen, human cartilage gp-39 (HC-gp-39) has been described. Defining the parameters of the autoimmune response may facilitate diagnosis and formulation of novel therapeutic strategies. For example, if the determinant(s) of HC gp-39 or other cartilage antigens recognized in the context of human MHC alleles were known, specific strategies for immune intervention could be designed which would interfere specifically with the autoimmune response. For the most part, determinant mapping studies of patients with T cell-mediated autoimmune diseases like RA and Multiple Sclerosis (MS) have failed to provide clear results and studies on inbred mouse strains have so far usually focused on determinant utilization in the context of murine MHC haplotypes and so may not pertain to humans. I propose to overcome this limitation for the experiments described in this application by using mice that have been engineered to express human MHC class II alleles including the RA susceptibility alleles HLA-DR4 (HLA-DRB1 0401) and HLA-DRW 14 (HLA-DRB1 0404), which will thus create a murine immune system with humanized antigen presentation properties. Our experiments will test the hypothesis that T cell recognition of human collagen type II and HC gp-39 epitopes are of importance in induction and/or propagation of polyarthritis in HLA-DR4 and HLA-DR14 transgenic mice, and whether intra-and intermolecular spreading of T cell responses are of significance in the propagation of polyarthritis. Based on this information, we will then be in a position to monitor responses in patients and design strategies for specific immune intervention. This essential information cannot be obtained by testing conventional mouse strains, nor through human studies, but it can readily be obtained through the use of humanized mice as proposed in this study.